[Polygenic risk score in personalized screening of lung cancer: a prospective cohort study in Chinese]

Objective: To explore how to personalize lung cancer screening programs for prevention in Chinese populations based on individual genetic risk score. Methods: We constructed the lung cancer polygenic genetic risk score (PRS-19) based on the 19 previously published genetic variations, using 100 615 participants with genotyping data from the China Kadoorie Biobank (CKB). Using the 5-year absolute risk of lung cancer in a population (55 years old with at least 30-pack-year history of smoking) as reference, the trend of 5-year absolute risk in different genetic risk groups was calculated in smokers and non-smokers, respectively. Distribution curves of 5-year absolute risk were also described to determine the theoretical age or smoking dose when different genetic risk groups reached the reference values. Given the overall findings, the specific start age for lung cancer screening were suggested for different genetic risk groups. Results: The 5-year absolute risk of lung cancer was 0.67% in 55-year-old smokers with 30 packs per year in the CKB. Among smokers, 5-year absolute risk of participants increased as the genetic risk increased. Hence, it was recommended that people at high genetic risk should start screening earlier. For the highest genetic risk populations (the top 1% of PRS), the start age might be changed to 50 years old. If the start age remained at 55-year-old, the smoking dose should be set lowered in high genetic risk populations. For the highest genetic risk populations, they should be included in lung cancer screening regardless of the cumulative smoking exposure. Among nonsmokers, it was also valuable to screen people with high genetic risk, considering the start age of 62 for the highest genetic risk populations and 74 for the lowest genetic risk populations (the bottom 5% of PRS). Conclusions: PRS-19 can be effectively used in developing lung cancer screening program for individualized prevention in China. For smokers with high genetic risk, the recommended starting age and smoking dose could be lowered for lung cancer screening, and non-smokers with high genetic risk could also be included in the screening programs.